Abstract Body: Alcohol abuse and peripheral artery disease (PAD) are independent contributors to skeletal muscle damage; both characterized by mitochondriopathy. We recently showed that muscle structural damage is exacerbated in PAD patients with a history of heavy alcohol use, however, potential underlying mechanisms remain unexplored. Methods: We compared key markers of oxidative stress and mitochondrial electron transport chain (ETC) abundance in gastrocnemius muscle biopsies from PAD patients with heavy alcohol use (>14 or > 7 drinks/week, for males and females, respectively, n = 7) with PAD patients (n = 6) and non-PAD controls (n = 5) consuming moderate to low or no alcohol. The intramuscular content of alcohol dehydrogenase 1B (ADH1B), responsible for alcohol catabolism to reactive aldehydes, and aldehyde dehydrogenase 2 (ALDH2), which subsequently degrades toxic aldehydes, were also assessed. Results: Irrespective of drinking status, muscle oxidative stress (4-hydroxynonenol (4-HNE) and protein carbonyls) was significantly greater in PAD patients compared to non-PAD controls (P < .01). Mitochondrial ETC Complex I (CI) protein was also reduced in PAD muscle (P = .0008). Nevertheless, 4-HNE accumulation (P = .0002) and the extent of ETC CI loss (P = .0373) was significantly greater in heavy-drinking PAD (PAD-HD) patients compared to low to moderate drinkers (PAD-LD). The loss of ETC components was also more extensive in PAD-HD muscle and included reductions in all five complexes (P < .05). When the alcohol-metabolizing enzymes were assessed, PAD-HD muscle only showed a significant increase in ADH1B compared to control (P = .0314) and PAD-LD muscle (P = .0423). Interestingly, ALDH2 was unaltered in PAD-HD patients (P = .7777). but was significantly increased in PAD-LD compared to controls (P = .0041) and PAD-HD (P = .0087). Conclusions: Although traditionally known for regulating the breakdown of alcohol-derived toxic metabolites, ALDH2 also plays a key role in the removal of other reactive aldehydes, including those generated consequent to mitochondrial oxidative stress, such as 4-HNE and protein carbonyls. Considering ALDH2 was higher, and 4-HNE and ETC complex loss was lower in PAD-LD patients, an alcohol-derived dysfunction in ALDH2 may account for why intramuscular oxidative stress and mitochondriopathy was more extensive in PAD patients with heavy alcohol use. Thus, ALDH2 could be a promising therapeutic target to mediate oxidative stress in PAD patients.